Sydney, Australia, September 1, 2026
Kazia Therapeutics Limited has reported new preclinical and translational findings suggesting that its investigational oncology therapy paxalisib may help overcome immunotherapy resistance in microsatellite stable (MSS) and proficient mismatch repair (pMMR) colorectal cancer. The company reported that paxalisib monotherapy reduced tumor burden by 52% (p=0.035) in a preclinical model of MSS/pMMR colorectal cancer. In a separate study, combining paxalisib with an existing immune checkpoint inhibitor produced an additional 50% reduction in tumor volume compared with immunotherapy alone (p=0.022). Treatment was reported to be well tolerated in both studies, with no evidence of treatment-related toxicity. Based on these findings, Kazia is preparing to advance paxalisib into a Phase 2 clinical study evaluating the investigational therapy in patients with immunotherapy-resistant MSS/pMMR metastatic colorectal cancer.
Paxalisib Reduces Tumor Burden in Preclinical Models
The newly reported findings focus on a difficult-to-treat colorectal cancer population. MSS/pMMR tumors account for approximately 85% to 90% of metastatic colorectal cancer cases, according to Kazia, and have historically shown limited benefit from immune checkpoint inhibitor monotherapy. This contrasts with the smaller MSI-H colorectal cancer population, where immune checkpoint inhibitors have demonstrated meaningful clinical activity. In Kazia’s preclinical work, paxalisib demonstrated significant anti-tumor activity as a single agent, reducing tumor burden by more than half in the MSS/pMMR model. When paxalisib was combined with pembrolizumab, an immune checkpoint inhibitor, the combination produced a further reduction in tumor volume compared with pembrolizumab alone. The company described these findings as supporting a potential strategy to transform an immunotherapy-resistant tumor environment into one that is more responsive to immune-based treatment. The research also incorporated patient-derived tissue biopsies, a novel preclinical pMMR model and single-cell spatial epigenetic profiling. These approaches were used to investigate molecular, immune and epigenetic characteristics associated with paxalisib response. Kazia said the analyses identified cancer-specific signatures that may help explain how paxalisib could alter the tumor microenvironment and increase cancer immune visibility. The company is continuing a translational biomarker program intended to identify patients most likely to benefit from treatment and establish early indicators of biological response.
Mechanism Targets PI3K/Akt/mTOR and Immune Resistance
Paxalisib is an investigational, brain-penetrant inhibitor of the PI3K/Akt/mTOR pathway being developed across multiple cancer indications. Kazia’s development strategy centers on selectively reprogramming biological pathways associated with immune evasion, treatment resistance and cancer progression. In MSS/pMMR colorectal cancer, the company is evaluating whether modulation of this pathway can alter tumor biology sufficiently to improve the activity of immune checkpoint blockade. The reported preclinical combination results provide an experimental basis for investigating paxalisib together with pembrolizumab in a clinical setting, although the company cautions that preclinical findings may not predict clinical outcomes in humans. Kazia also reported that emerging biomarker findings and the preclinical data have contributed to a new patent filing covering aspects of paxalisib’s potential use in colorectal cancer, strengthening the intellectual property position of the program as it moves toward clinical development. The company characterizes the approach as potentially first-in-class, noting that, to its knowledge, no other PI3K/mTOR inhibitor has previously demonstrated meaningful activity in pMMR colorectal cancer.
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Phase 2 Study Planned for Immunotherapy-Resistant CRC
Kazia plans to initiate a five-arm Phase 2 clinical trial in previously treated MSS/pMMR metastatic colorectal cancer. The study is expected to evaluate paxalisib as monotherapy and in combination with pembrolizumab, with different paxalisib dose levels and a standard-of-care comparator. The planned primary endpoint is safety and tolerability, while secondary endpoints are expected to include progression-free survival (PFS), overall response rate (ORR) and overall survival (OS). Enrollment is anticipated to begin in the first quarter of 2027, with full enrollment across all five study arms expected by the end of 2027. Paxalisib is already being investigated across several oncology programs, including advanced breast cancer, brain metastases, diffuse midline gliomas and primary central nervous system lymphoma. The colorectal cancer program represents another potential application of the drug’s pathway-targeting strategy, with the upcoming Phase 2 study expected to provide the first clinical assessment of whether the promising preclinical immunotherapy-sensitizing effects can translate into meaningful patient benefit.
Source: Kazia Therapeutics press release
